Despite advances in our knowledge of Alzheimer?s disease (AD) course, our understanding of the pathogenesis of this devastating illness is lagging behind. Alzheimer?s disease (AD) is a highly complex multifactorial disease. To describe the complexity of its molecular pathways and identify new therapeutic targets, it requires an equally complex high resolution molecular profiling. This application achieves the goals of enhancing the discovery efforts of AMP-AD and M2OVE-AD (RFA-AG-17-054) by: (i) Generating additional layers of ?omics? and enhancing the data integration by using the same molecular profile platforms in both projects; and (ii) Applying new computational approaches (multi-omic integration) to discover predictive and translatable system-based biomarkers that can guide therapy development. Hence, we are proposing to add to one or both cohorts high- resolution metabolomics, lipidomics, and more detailed genomics. Our preliminary brain tissue analyses suggest that there are altered lipid and protein pathways in AD. Lipid alterations have been linked with vascular dysregulation. Studying vascular factors in AD is an objective of M2OVE-AD. We hypothesize that there are multi-layered network alterations detectable along the continuum of AD (pre-clinical, prodromal and dementia stages) and in various tissues. We hypothesize that there are multi-layered network alterations detectable along the continuum of AD (pre-clinical, prodromal and dementia stages) and in various tissues. Under Aim-, we will conduct genotyping, CSF proteomics and CSF/blood lipidomics on our ongoing M2OVE-AD subjects (n=250). Under Aim-2, we propose to conduct post-mortem brain and pre-mortem plasma lipidomics and metabolomic analyses on the Religious Order Study (ROS)/ Memory and Aging Project (MAP) participants. ROS/MAP is part of the Emory AMP-AD project. We then integrate under Aim-3, using newly developed computational methods the resulting data from the parent grants and from this proposal and identify large scale networks that are altered across the disease spectrum and across various tissues. Our deliverable form this project include: (i) a publicly available dataset to the scientific community (SYNAPSE website) of 2 highly phenotyped cohorts with multi-layer and multi-tissue molecular profile with broad coverage; (ii) Novel methods to integrate multi-layer molecular profiling to identify disease biomarkers (the multi-omic AD interactome).